Erythropoietin Stimulating Agents

Mechanism of Action

Endogenous EPO and ESAs E induce the division and differentiation of erythroid progenitor cells.[3] The surface of CD34+ hematopoietic stem cells (erythrocyte progenitor cells) contains EPO receptors. The binding of endogenous EPO or recombinant analogs creates a cellular signaling cascade, activating genes that promote cell proliferation and prevent apoptosis. The result is an elevation in total body hemoglobin and hematocrit. The continuous EPO receptor activator methoxy polyethylene glycol-epoetin β is a synthetic version of EPO that releases epoetin β slowly. This medication has a longer half-life than other ESAs and may be administered monthly.[5] Severe pre-transfusion anemia in ICU patients enhances the hemoglobin increment post-transfusion. During studies observing mice, EPO promoted RBC recovery post-transfusion, which is crucial for managing hypoxemia involving erythroid progenitors and macrophages.[7]

Pharmacokinetics

Absorption: Subcutaneous administration of epoetin alfa achieves peak plasma concentration (Cmax) within 5 to 24 hours. Darbepoetin has a bioavailability of approximately 37% in adults and 54% in children. Hemoglobin levels typically increase 2 to 6 weeks after starting treatment. The absolute bioavailability of methoxy polyethylene glycol-epoetin β after subcutaneous administration is 62%.

Distribution: The volume of distribution for epoetin alfa and methoxy polyethylene glycol-epoetin β is approximately 61 mL/kg. Darbepoetin is found in maximum concentrations in bone marrow or the injection site (skin), with subsequent distribution to the thyroid gland, kidneys, adrenal glands, spleen, lungs, stomach, and bladder.

Metabolism: EPO and epoetin alfa are internalized and degraded after binding to the EPO receptor (EPO-R). ESAs may also be cleared via the reticuloendothelial and lymphatic systems. The removal of EPO's oligosaccharide side chains primarily occurs in the liver. Methoxy polyethylene glycol–epoetin β has a structure similar to epoetin but is enhanced with a water-soluble polyethylene glycol group. Pegylation increases its molecular weight, enhancing its solubility and protecting it from enzymatic breakdown.

Excretion: Epoetin-alpha has a half-life of 6 hours after intravenous administration and 24 hours after subcutaneous administration.[8] The average terminal half-life of darbepoetin in adults after subcutaneous administration (t_1/2 = 48.4 h) exceeds that of intravenous (t_1/2 = 25.3 h). This phenomenon (termed "flip-flop kinetics") is observed when a drug's absorption is significantly slower than its elimination, causing its persistence in the body to be chiefly influenced by absorption rather than elimination.[9][10] Pegylated methoxy polyethylene glycol–epoetin β demonstrates reduced renal clearance. This structural modification extends its half-life to approximately 130 hours following subcutaneous or intravenous administration.[11] Importantly, half-life and other pharmacokinetic parameters vary based on factors such as chemotherapy, CKD, age, and route of administration.

Administration

Available Dosage Forms and Strengths 

• ESAs are typically sourced from transfected Chinese hamster ovary cells (CHOs) during large-scale manufacturing protocols.[3] An isotonic solution buffers the ESA powder, which the provider can administer intravenously or subcutaneously. 
• Darbepoetin is available in 25 μg, 40 μg, 60 μg, 100 μg, and 200 μg single-dose powder vials and premixed, single-dose syringes with the following powder and buffer dilutions: 10 μg in 0.4 mL, 25 μg in 0.42 mL, 40 μg in 0.4 mL, 60 μg in 0.3 mL, 100 μg in 0.5 mL, 300 μg in 0.6 mL, and 500 μg in 1 mL.
• Epoetin alfa is available in 2,000 IU/mL, 3,000 IU/mL, 4,000 IU/mL, and 10,000 IU/mL single-dose vials. Additionally, it is available in 10,000 IU/mL and 20,000 IU/mL multiple-dose vials containing benzyl alcohol. 
• Methoxy polyethylene glycol-epoetin β is available in 30 μg, 50 μg, 75 μg, 100 μg, 120 μg, 150 μg, 200 μg, or 250 μg in 0.3 mL solution in single-dose, prefilled, injectable syringes. A 360 μg in 0.6 mL solution is also available in a single-dose prefilled syringe for once-monthly administration.

Adult Dosing

Below are the standard dosing protocols for ESA administration. Dosing and frequency can be adjusted based on response to treatment. Specific and alternate protocols should be verified via manufacturer information or institutional protocols.

Epoetin alfa:

• CKD-associated anemia: Start with 50 to 100 units/kg (intravenously or subcutaneously), 3 doses/week. Intravenous dosing is preferred for patients on hemodialysis.
• HIV-associated anemia: Start with 100 units/kg/dose (intravenously or subcutaneously), 3 doses/week. The maximum dosing is 300 units/kg/dose, 3 doses/week.
• Chemotherapy-related anemia: Start with 40,000 units subcutaneously once weekly or 150 units/kg/dose subcutaneously, 3 doses/week.
• Surgery-associated transfusion reduction: 300 units/kg/dose subcutaneous daily for 15 days

Darbepoetin alfa:

• CKD-associated anemia: Start with 0.45 μg/kg (intravenously or subcutaneously) once weekly.
• Chemotherapy-related anemia: Start with 2.25 μg/kg/dose subcutaneously once weekly or 500 μg subcutaneously every 3 weeks.

Methoxy polyethylene glycol-epoetin β:

Before initiating this medication, ensure the patient's hemoglobin level is stable on current epoetin or darbepoetin dosing. The patient's iron status should be determined before and routinely during ESA therapy. Supplemental iron should be given if serum ferritin is <100 μg/L or transferrin saturation is <20%.

• Patients not currently undergoing ESA therapy:
  • On dialysis: Start with 0.6 μg/kg once every 2 weeks.
  • Not on dialysis: Start with 1.2 μg/kg subcutaneously monthly. Alternatively, a 0.6 μg/kg (intravenously or subcutaneously) starting dose can be administered once every 2 weeks.
• Conversion from another ESA:
  • Adjust dosing to once monthly or once every 2 weeks based on the total weekly dose of epoetin alfa or darbepoetin alfa at the time of conversion.

Specific Patient Populations

Hepatic impairment: The manufacturer's label for epoetin alfa, methoxy polyethylene glycol-epoetin β, and darbepoetin does not provide dosage adjustments. Metabolic-associated fatty liver disease and advanced liver fibrosis were not found to correlate with hypo-responsiveness to ESAs independently. However, the higher FIB-4(Fibrosis-4) score observed in the ESA hypo-responsive group and the association between liver stiffness measurement and ESA hypo-responsiveness suggests that liver fibrosis could be a potential clinical indicator of ESA hypo-responsiveness.[12]

Renal impairment: Epoetin alfa, methoxy polyethylene glycol-epoetin β, and darbepoetin are indicated for chronic kidney anemia, as mentioned above. A post-marketing study assessed long-term darbepoetin in Japanese patients with non-dialysis CKD. Cardiovascular adverse events occurred in 12.6% of the study population. Higher hemoglobin levels (≥11 g/dL) were associated with fewer composite renal endpoints without an increase in cardiovascular adverse events (p < 0.0001).[13] 

Pregnancy considerations: Epoetin alfa is the preferred ESA during pregnancy due to comprehensive safety data compared to other agents.[14] Epoetin alfa should be considered for severe anemia in iron-replete patients who are not responding adequately to intravenous iron alone. Multi-use vials containing benzyl alcohol must not be administered to women who are pregnant or lactating; single-use vials without benzyl alcohol are preferred. Darbepoetin alfa should be used cautiously in women who are pregnant and on dialysis due to limited safety data. Successful outcomes have been reported with weekly doses up to 100 μg, but risks and benefits must be carefully weighed. Methoxy polyethylene glycol has limited use for pregnant women, with few successful outcomes documented. Further research is needed to establish its safety profile compared to epoetin alfa.

Breastfeeding considerations: 

EPO is naturally present in human milk and may support mammary epithelial and infant gastrointestinal tract health, hypothetically reducing the risk of HIV transmission.[15][16] Epoetin alfa has been determined safe for women who are breastfeeding. Some study data suggest improved postpartum anemia response when epoetin alfa is combined with iron therapy, but the current consensus indicates it does not clinically enhance hemoglobin levels over iron alone. No adverse effects have been reported in breastfed infants whose mothers received epoetin alfa. Due to the benzyl alcohol content, the manufacturer recommends avoiding multiple-dose vials during lactation and delaying breastfeeding for 2 weeks after any dose containing benzyl alcohol. No special precautions are needed for breastfeeding women and taking epoetin alfa from single-use vials without preservatives.

The excretion of darbepoetin alfa into breast milk and its effects on breastfed infants have not been specifically studied. Darbepoetin alfa is immunologically and biologically similar to native EPO. Intravenous administration of darbepoetin alfa to newborn infants has been safely conducted using doses exceeding those anticipated to be excreted into breast milk. Therefore, no special precautions are necessary while breastfeeding.[17] The excretion of methoxy polyethylene glycol-epoetin β into breast milk has not been studied. Due to the lack of specific data on methoxy polyethylene glycol-epoetin β in breastfeeding, an alternative medication may be preferable, particularly when nursing a newborn or preterm infant.[18]

Pediatric patients:

In a randomized multicenter study, preterm infants receiving darbepoetin or EPO showed improved cognitive outcomes at 18 to 22 months compared to placebo. These ESAs were associated with higher cognitive scores and better cognitive permanence.[19] Epoetin alfa is recommended for patients 1 month and older with CKD-associated anemia. However, its safety and effectiveness have not been established for patients younger than 1 month. Epoetin alfa is recommended for patients 5 and older with chemotherapy-related anemia, but its safety and efficacy have not been established for patients younger than 5. Darbepoetin alfa is indicated for patients with CKD who are 1 month or older. However, its safety and effectiveness have not been established for patients younger than 1 month, and its use in pediatric cancer has not been established.

Methoxy polyethylene glycol-epoetin β appears to have a favorable safety profile.[20] This medication benefits patients with anemia who are 3 months or older after stabilization with another ESA. This benefit is independent of dialysis status. However, its safety and effectiveness have not been established in patients younger than 3 months. Continuous EPO receptor activator/methoxy polyethylene glycol-epoetin β is associated with stable hemoglobin levels in pediatric patients with CKD who are on dialysis.

Older patients: Careful consideration is necessary when selecting the ESA dose, and providers are encouraged to start at the lower end of the dosing spectrum. This approach acknowledges the higher incidence of compromised hepatic, renal, or cardiac function and the presence of concurrent illnesses or medications in older adults.

Adverse Effects

The most severe adverse effects of EPO are related to a significant risk of thrombotic events, particularly in surgical patients.[3] Supplemental use of ESAs increases blood viscosity. Given this, as well as the reduced vasodilatory effect due to a low baseline pO₂, there is an associated increased risk of ischemic stroke and myocardial infarction.[21] There is also an increased risk of venous thromboembolism, and some have proposed the use of antithrombotic prophylaxis in patients receiving ESA therapy.[3] There is also concern regarding the potential progression of tumorigenesis in patients with certain forms of cancer, particularly breast cancer, non-small cell lung cancer, head and neck cancer, lymphoid cancer, and cervical cancer.[22] This occurs through increased cell signaling and tumor angiogenesis. In a multicenter study, nausea, vomiting, diarrhea, fatigue, insomnia, peripheral edema, thrombocytopenia, myalgias, arthralgias, rashes, abdominal pain, headache, and paresthesias were common adverse effects experienced by patients undergoing chemotherapy and epoetin alfa treatment.[23]

Drug-Drug Interactions

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs): Due to synergism, concurrent administration of ESA with HIF-PHIs, such as roxadustat and vadadustat, is not advisable.

ACE inhibitors: In a study of 660 hemodialysis patients, ACE inhibitor therapy was associated with lower hemoglobin levels (p=0.02) and higher EPO resistance in those with the ACE gene D/D genotype (p=0.006). Additional research is required.[24]

Angiotensin receptor blockers: In 1 study, researchers explored the effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers on erythropoiesis in hemodialysis patients and healthy controls. They observed that angiotensin receptor blockers significantly reduced the formation of erythroid progenitor colonies (burst-forming units-erythroid) in both groups, whereas ACE inhibitors had a lesser impact. This suggests that ARB-mediated AT1 receptor blockade directly inhibits erythropoiesis in vitro. Further research is required.[25]

Contraindications

Epoetin alfa, darbepoetin, and methoxy polyethylene glycol-epoetin β are contraindicated for patients with uncontrolled hypertension, pure red cell aplasia (PRCA), and severe allergic reactions. EPO-stimulating agents are contraindicated for patients with hypersensitivity to non-human mammal-derived products because of ESA production methods.[3] ESAs containing benzyl alcohol are contraindicated for neonates, peripartum mothers, and breastfeeding mothers due to the risk of gasping syndrome. This syndrome causes gasping respiration, renal failure, and neurological deterioration in neonates, resulting from severe metabolic acidosis.[26]

Box Warnings

ESAs increase mortality, myocardial infarction, thrombosis of vascular access, stroke, venous thromboembolism, and tumor progression or recurrence in certain patient populations.[27][28]

CKD: Patients who were given ESAs to achieve a hemoglobin level above 11 g/dL were at a higher risk of death, serious adverse cardiovascular events, and stroke. Providers should administer the lowest ESA dose sufficient to reduce the need for red blood cell transfusions.

Cancer: ESAs are associated with decreased overall survival and increased risk of tumor progression/recurrence in patients with non-small cell lung, head and neck, lymphoid, cervical, and breast cancers. Providers should administer the lowest effective ESA dose to decrease the risk of RBC transfusions and serious cardiovascular and thromboembolic reactions. ESAs should only be used to manage anemia caused by myelosuppressive chemotherapy. They should not be prescribed for patients undergoing myelosuppressive chemotherapy with the intention of cure. ESAs are discontinued following the completion of a chemotherapy course.

Warning and Precautions

Thromboembolic events: The American College of Cardiology/American Heart Association (ACC/AHA) 2022 guidelines note that anemia in heart failure (HF) is associated with impaired EPO production and is linked to worse long-term outcomes. Although initial small study data suggested the potential benefits of ESAs for improving functional capacity and reducing hospitalizations in patients with HF, there is a risk of thromboembolic events, including stroke.[29] In patients with HF and anemia, ESAs should not be prescribed to improve morbidity and mortality.[30] Physicians should exercise caution when prescribing ESAs to patients with a history of deep vein thrombosis (DVT), pulmonary embolism, or hypercoagulability disorder. Similar caution is warranted for patients with a history of ischemic stroke or cardiovascular disease, owing to the potential increase in blood viscosity associated with ESA use.[21]

Pure red cell aplasia (PRCA): Characterized by severe anemia and low reticulocyte count, PRCA has been reported in postmarketing to be associated with neutralizing antibodies against EPO, along with methoxy polyethylene glycol-epoetin β, darbepoetin, and epoetin. This risk is prominent in patients with CKD who are administered ESAs subcutaneously. PRCA has also occurred in patients receiving ESAs for hepatitis C-related anemia, a use that the FDA has not approved.[31][32] PRCA has been observed in patients receiving darbepoetin alfa and epoetin alfa therapy. ESA therapy should be discontinued in patients who develop severe anemia and low reticulocyte count during treatment, and the presence of EPO-neutralizing antibodies should be determined. ESAs should be discontinued permanently if PRCA develops. Switching to another ESA is not advisable as it may lead to cross-reactivity due to antibody formation.

Seizures: ESAs increase the risk of seizures in patients with CKD. These patients should be monitored closely for neurologic symptoms during treatment initiation. New-onset seizures, premonitory symptoms, or altered seizure frequency should prompt emergency medical attention.[33]

Allergic reactions: Severe allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria, have been reported in patients receiving methoxy polyethylene glycol–epoetin β, darbepoetin alfa, and epoetin alfa. Patients should be monitored closely for clinical signs and symptoms. Providers should immediately discontinue treatment and administer appropriate therapy if such reactions occur.

Severe cutaneous adverse drug reactions: Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis have been reported in patients treated with ESAs.[34]

Potential for abuse: Although ESAs are not controlled substances, they may be used by athletes for performance-enhancing purposes.[35]

Dialysis monitoring:  The initiation of ESAs may require an increased dosage of heparin for anticoagulation to prevent clotting of the extracorporeal circuit during hemodialysis. One study identified higher doses of ESAs and doxazosin as risk factors requiring further research.[36]

Monitoring

Patients receiving EPO-stimulating agent therapy should have baseline hemoglobin and transferrin levels documented before initiating.[3] Hemoglobin should be checked weekly after beginning treatment. The dosing and administration frequency should be adjusted based on the response to treatment. Providers should withhold treatment if hemoglobin rises to a non-anemic level.[37] Iron supplementation should be considered in patients with poor response to ESA therapy, as iron availability may be inadequate.[3] According to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, ESAs increase iron utilization and decrease serum iron, TSAT, and ferritin levels. They also suppress hepcidin by inducing erythropoiesis, increasing iron supply from macrophage stores and dietary sources. ESA stimulation can lead to or exacerbate iron deficiency by creating a high demand for iron that exceeds available stores. This may occur despite adequate initial iron levels, especially during inflammation, which elevates hepcidin and restricts iron release. Therefore, the patient's response to ESA therapy depends on iron status and inflammatory severity. Monitoring reticulocyte hemoglobin content within 3–4 days of iron therapy initiation provides information regarding effective iron incorporation into red blood cells, aiding in tailoring iron and ESA therapy.

According to ASCO/ASH guidelines, for patients with non-Hodgkin lymphoma, myeloma, or chronic lymphocytic leukemia, clinicians should monitor the hematologic response to cancer treatment before considering an ESA. Caution is advised when using ESAs concomitantly with treatments/diseases that increase the risk of thromboembolic complications. Before initiating ESA therapy, healthcare providers should conduct a comprehensive assessment, including a review of the patient's medical history, physical examination, and diagnostic tests to identify and treat other potential causes of anemia apart from chemotherapy or underlying blood-related cancers. This assessment may involve examining a peripheral blood smear, conducting iron studies (including iron levels, total iron-binding capacity, transferrin saturation, and ferritin), checking for folate and vitamin B12 levels, assessing the reticulocyte count, looking for signs of hidden blood loss, evaluating renal function, measuring baseline EPO levels, and checking serum thyroid-stimulating hormone levels when necessary. Additionally, some patients may require direct antiglobulin testing, such as the Coombs test.[4]

Vitamin B6 deficiency should be considered in pediatric patients on hemodialysis who are not responding to ESA and iron therapy. Supplemental vitamin B6-corrected anemia can improve hemoglobin levels without further transfusions.[38] One study suggests that erythrocyte creatine content could be a promising predictor of anemia improvement in maintenance hemodialysis patients receiving ESAs. However, further research is needed to validate its clinical utility and optimize its application in practice.[39]

Toxicity

Signs and Symptoms of Overdose

Most EPO-stimulating agent toxicity cases are related to the adverse effects of chronic use. There are few case reports of acute toxicity. One involved a man who intentionally injected himself with recombinant human EPO, causing his hemoglobin to rise to a dangerously high level.[40] Cases of severe hypertension have been reported following ESA overdosage. Another study linked Environmental Protection Agency (EPA) water supply data with patient records from the United States Renal Data System (USRDS), revealing that even low levels of lead in community water systems are associated with decreased hemoglobin levels and increased use of ESAs in patients with end-stage kidney disease (ESKD).[41]

Management of Overdose

Patients should receive supportive care for hypertension, intravenous fluids, and serial phlebotomy. Severe cases may require erythrocytapheresis.[42]

Enhancing Healthcare Team Outcomes

Treating anemia in patients using ESAs requires an interprofessional team of medical providers. This team should include a nephrologist for patients with CKD, a hematologist/oncologist overseeing chemotherapy, appropriate nursing staff, a pharmacist for ESA dosing, and a phlebotomy or laboratory technician for blood sampling to monitor for improvement. The interprofessional team should arrange appropriate follow-up appointments to reassess the patient's health status and any adverse effects of the ESA; this is where specialty-trained nurses and pharmacists can play a significant role. Nurses have the most frequent contact with the patient while educating, monitoring for adverse effects, and administering the medication. Pharmacists with specialty oncology certification should monitor dosing, interactions, and lab values that may alter or stop the dosing of the ESA. Both nurses and pharmacists must chart and inform the treating physician of any findings, changes, or concerns.

Patients should receive counseling on the potential adverse effects and when to seek immediate medical care. Emergency medical providers should be aware of the adverse effects of ESAs to risk-stratify patients for venous thromboembolism, acute coronary syndrome, ischemic stroke, and other emergent conditions related to ESA. Only through the coordinated effort of an interprofessional healthcare team can ESA therapy be administered safely and effectively, with minimal adverse events and optimal patient results.

Monitoring the hemoglobin level to optimize patient outcomes and minimize adverse effects is very important. A debate exists regarding the appropriate target hemoglobin in individuals treated with ESA. A pooled analysis of 9 randomized control trials on patients with CKD indicates that patients have higher mortality and morbidity from cardiovascular-related events when the patient's hemoglobin falls below 10 g/dL.[43] This pooled analysis showed no survival benefit for patients treated with ESA when the hemoglobin exceeded 13 g/dL. However, there was a higher incidence of adverse events such as hypertension, vascular access thrombosis, and stroke. Current guidelines advocate for tailoring target hemoglobin levels to individual needs. Optimal levels typically range between 11 and 12 g/dL, considering that higher doses of ESAs can increase the risk of thrombotic events. An interprofessional team approach and communication among clinicians (MDs, DOs, NPs, PAs), hematologists, pharmacists, and nurses are crucial to decreasing potential adverse effects and improving patient outcomes related to ESA.